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Lysophosphatidic Acid Receptors LPAR5 and LPAR2 Inversely Control Hydroxychloroquine-Evoked Itch and Scratching in Mice.
Fischer, Caroline; Schreiber, Yannick; Nitsch, Robert; Vogt, Johannes; Thomas, Dominique; Geisslinger, Gerd; Tegeder, Irmgard.
Afiliación
  • Fischer C; Institute for Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.
  • Schreiber Y; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt am Main, Germany.
  • Nitsch R; Institute for Translational Neuroscience, Medical Faculty, WWU Münster, 48149 Münster, Germany.
  • Vogt J; Department of Molecular and Translational Neurosciences, Institute for Anatomy and Center of Molecular Medicine Cologne (CMMC), and Cologne Excellence Cluster for Aging associated Diseases (CECAD), University of Cologne, 50923 Köln, Germany.
  • Thomas D; Institute for Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.
  • Geisslinger G; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt am Main, Germany.
  • Tegeder I; Institute for Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.
Int J Mol Sci ; 25(15)2024 Jul 26.
Article en En | MEDLINE | ID: mdl-39125747
ABSTRACT
Lysophosphatidic acids (LPAs) evoke nociception and itch in mice and humans. In this study, we assessed the signaling paths. Hydroxychloroquine was injected intradermally to evoke itch in mice, which evoked an increase of LPAs in the skin and in the thalamus, suggesting that peripheral and central LPA receptors (LPARs) were involved in HCQ-evoked pruriception. To unravel the signaling paths, we assessed the localization of candidate genes and itching behavior in knockout models addressing LPAR5, LPAR2, autotaxin/ENPP2 and the lysophospholipid phosphatases, as well as the plasticity-related genes Prg1/LPPR4 and Prg2/LPPR3. LacZ reporter studies and RNAscope revealed LPAR5 in neurons of the dorsal root ganglia (DRGs) and in skin keratinocytes, LPAR2 in cortical and thalamic neurons, and Prg1 in neuronal structures of the dorsal horn, thalamus and SSC. HCQ-evoked scratching behavior was reduced in sensory neuron-specific Advillin-LPAR5-/- mice (peripheral) but increased in LPAR2-/- and Prg1-/- mice (central), and it was not affected by deficiency of glial autotaxin (GFAP-ENPP2-/-) or Prg2 (PRG2-/-). Heat and mechanical nociception were not affected by any of the genotypes. The behavior suggested that HCQ-mediated itch involves the activation of peripheral LPAR5, which was supported by reduced itch upon treatment with an LPAR5 antagonist and autotaxin inhibitor. Further, HCQ-evoked calcium fluxes were reduced in primary sensory neurons of Advillin-LPAR5-/- mice. The results suggest that LPA-mediated itch is primarily mediated via peripheral LPAR5, suggesting that a topical LPAR5 blocker might suppress "non-histaminergic" itch.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Prurito / Ratones Noqueados / Receptores del Ácido Lisofosfatídico / Hidroxicloroquina Límite: Animals Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Prurito / Ratones Noqueados / Receptores del Ácido Lisofosfatídico / Hidroxicloroquina Límite: Animals Idioma: En Revista: Int J Mol Sci Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Suiza